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In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 9 ( 2020-09), p. 2354-2363

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-0959-x

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2008023-2

In: Hematological Oncology, Wiley, Vol. 36, No. 4 ( 2018-10), p. 624-632

Abstract: The Bruton tyrosine kinase inhibitor ibrutinib (IB) has attained an important role in the treatment of patients with chronic lymphocytic leukaemia, mantle cell lymphoma, and Waldenström macroglobulinemia, significantly improving clinical outcomes. However, IB therapy has been associated with an increased risk of atrial fibrillation (AF) and bleeding. We report on the expert opinion that a group of Italian haematologists, cardiologists, and pharmacologists jointly released to improve the practical management of patients at risk for AF and bleeding during treatment with IB. A proper pretreatment assessment to identify patients who are at a higher risk, careful choice of concomitant drugs, regular monitoring, and multispecialist approach were characterized as the main principles of clinical management of these patients. For patients developing AF, anticoagulant and antiarrhythmic therapy must be guided by considerations about efficacy, safety, and risk of pharmacokinetic interactions with IB. For patients experiencing bleeding or requiring procedures that increase the risk of bleeding, considerations about platelet turnover, IB‐related platelet dysfunctions, and bleeding worsening by concomitant anticoagulants or antiplatelet agents provide clues to manage bleeding. Overall, AF and bleeding are manageable clinical events in patients receiving IB, not requiring drug interruption in most cases. Preexisting AF should not represent an absolute contraindication to IB therapy. For each patient candidate for IB, strategies of risk assessment and mitigation may allow to exploit the life‐saving effects of in chronic lymphocytic leukaemia and mantle cell lymphoma.

Type of Medium: Online Resource

ISSN: 0278-0232 , 1099-1069

URL: Issue

URL: Article

DOI: 10.1002/hon.v36.4

DOI: 10.1002/hon.2503

Language: English

Publisher: Wiley

Publication Date: 2018

detail.hit.zdb_id: 2001443-0

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3147-3147

Abstract: Introduction. Observational, real-life studies are relevant to understand whether data derived from prospective controlled trials (CTs) are reproducible in the day-to-day clinical practice. Within a named patient program (NPP), free and early access to ibrutinib was made available for the treatment of relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL) until this agent was approved in Italy. To define the efficacy and toxicity profile of patients treated with ibrutinib in this real-life setting, the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) group carried out a retrospective analysis on the outcome of R/R patients with CLL who received ibrutinib in the NPP. Methods. Between April 2014 and January 2015, 216 R/R patients with CLL managed at 20 centers in Italy were included in the NPP. Patients were required to have R/R disease with disease progression within 24 months after prior chemo-immunotherapy. All patients received ibrutinib at the standard dose of 420 mg daily, continuously until disease progression or unacceptable toxicity. The period of observation included the duration of the NPP and was extended up to January 2016 for patients still on treatment with the commercial drug. Clinical data were reported retrospectively by the treating physicians using the Research Electronic Data Capture (REDCap) system. Results. The median age of patients was 58.3 years (range 27.5-81); 89% of patients were in Binet stage B-C. The median number of prior treatments was 3 (range 1-14). Thirty-seven % of patients was refractory to prior treatment. Deletion 17p and/or TP53 mutations were found in 54% of patients and deletion 11q in 11.6%. Seventy-eight % of patients had an unmutated IGHV gene profile. Prior atrial fibrillation (AF) was reported in 13 cases (6%), while 7 patients with AF (3.3%) were on anti-arrythmic treatment. Hypertension was recorded in 76 cases (35.2%). The median follow-up of patients was 24 months (range, 1-24 months. A response to ibrutinib was observed in 172 patients (79.6%) with a clinical CR/CRi in 34 (15.7%) and a PR/PR-L in 138 (63.9%). Similar response rates were observed in patients with an unmutated IGHV gene status (82.1%) and in those with deletion 17p/TP53 mutations (79.6%). The progression-free survival (PFS) and overall survival (OS) at 24 months were 64.6% (95%CI: 58.0-71.9) and 72.7% (95%CI: 66.5-79.4), respectively. No differences in PFS and OS were observed according to the IGHV mutational status (IGHV unmutated vs mutated: PFS, 65.2% vs 61.0%; p=0.7; OS, 65.2% vs 72.0%, p=0.6) and the presence of TP53 aberrations (TP53 aberrations, present vs absent: PFS, 64.8% vs 64.1%; p=0.6; OS, 69.8% vs 72.7%; p=0.8). Forty-eight patients (22.2%) discontinued ibrutinib within 12 months and 22 (10.2%) within 12-24 months from the start of ibrutinib. Progressive disease and Richter syndrome were the most common reasons for discontinuation that accounted for 16.2% (35 patients) and 1.8% (4 patients) of cases, respectively, and occurred after a median of 17 months from the start of ibrutinib. Treatment discontinuations due to adverse events (AEs) were recorded in 25 patients (11.6%) after a median time of 6 months from the start of treatment and included infections/febrile events in 7 cases, bleeding events in 3 (intracranial hemorrhage 1), sudden death in 3, acute myocardial infarction in 1, ischemic stroke in 2, second malignancy in 3, diarrhea in 1. AF occurred during treatment in 14 (6.5%) patients and was the reason of ibrutinib discontinuation in 2. AEs leading to discontinuation was not specified in 3 cases. Other reasons for ibrutinib discontinuation in 6 (2.8%) patients were ASCT in 4, unplanned surgery in 1, unknown in 1. Survival probability at 12 months from treatment discontinuation due to AEs or DP/RS was 38.2 and 37.2 months respectively (p= 0.6). Conclusions. The results of this real-life study show that in unselected patients with R/R CLL the clinical activity of ibrutinib was comparable to that reported in CTs. However, a third of patients discontinued ibrutinib within 24 months from the start of treatment. An earlier introduction of ibrutinib in the treatment approach of R/R patients, a careful surveillance and management of toxicities will optimise the clinical benefits of ibrutinib in CLL patients treated in the clinical practice. Disclosures Mauro: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zinzani:TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; MSD: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Cortelezzi:novartis: Consultancy; roche: Consultancy; abbvie: Consultancy; janssen: Consultancy. Carlo-Stella:AstraZeneca: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau; Sanofi: Consultancy; ADC Therapeutics: Research Funding, Speakers Bureau; Boehringher Ingelheim Italia: Consultancy; Genenta Science: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Amgen: Speakers Bureau; MSD Italia: Speakers Bureau. Molica:Roche: Other: Advisory board; Gilead: Other: Advisory board; Jansen: Other: Advisory board; AbbVie: Other: Advisory board. Coscia:Janssen, Karyopharm: Research Funding; Abbvie, Gilead, Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zaja:Janssen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Sandoz: Honoraria; Abbvie: Honoraria. Gaidano:Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Morphosys: Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Gobbi:Ariad: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Amgen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees. Cuneo:janssen: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau. Foà:JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; NOVARTIS: Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; CELTRION: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-118280

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 16 ( 2015-10-15), p. 1921-1924

Abstract: CLL patients harboring mutated IGHV genes but neither 11q or 17p deletion experience durable remission after frontline FCR.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2015-05-647925

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3300-3300

Abstract: Background. Fludarabine, cyclophosphamide, and rituximab (FCR) has represented a significant advancement in the treatment of patients with chronic lymphocytic leukemia (CLL) and has the potential of inducing durable remissions of the disease. In the new scenario of targeted agents for CLL, there is an increasing interest in identifying patients who may gain the maximum benefit in terms of disease control by a single shot of FCR chemo-immunotherapy. Purpose. Here we aimed at identifying predictors of durable remission after first line FCR treatment. Methods. The study was based on 405 progressive and previously untreated CLL patients who consecutively received standard FCR (up to 6 cycles) as first line therapy in 19 hematologic centers between 2001 and 2010. According to an intention to treat approach, all patients who received at least one FCR cycle were registered in the study. This series was representative of a FCR treated CLL cohort with respect to baseline characteristics, including age (median: 61 years; 〉 65 years in 33% of patients), gender (male in 68% of patients), stage (progressive Binet A in 11% of patients; Binet B in 59%; Binet C in 30%) and number of FCR courses (median: 6; 〈 6 in 42% of patients). Most patients were evaluable for IGHV mutation status (unmutated in 192/296, 65%) and genomic aberrations at treatment requirement (17p deletion in 30/306, 9.8%; 11q deletion in 56/300, 19%; +12 in 70/298, 23%; 13q deletion in 108/301, 36%). Results. After a median follow-up of five years, 159 patients have progressed and 72 have died, accounting for a 5-year progression free survival (PFS) according to the IWCLL criteria of 47% (median: 58 months) and for a 5-year overall survival (OS) of 81% (median: not reached). When the demographic effects of age, gender and year of treatment were compensated, the 5-year and 10-year survival of the whole CLL cohort were 85% and 68%, respectively, of those expected in the matched normal general population (p 〈 0.001). By multivariate analysis, unmutated IGHV genes, 11q deletion and 17p deletion maintained independent association with both PFS and OS, thus providing the rationale to utilize them in the development of a model to predict remission duration after FCR. By recursive partitioning analysis, 17p deletion was the most important variable in predicting PFS after FCR, followed by 11q deletion and IGHV mutation status (Fig. 1A). Based on the application of an amalgamation algorithm, cases harboring unmutated IGHV genes and 11q deletion were grouped into a single category because they showed an identical drop of the PFS curve (Fig. 1A). By this approach, three CLL subgroups were hierarchically classified. Clinical features and treatment indication were superimposable across the three risk groups. The low risk category comprised patients harboring mutated IGHV genes but neither 11q or 17p deletion, and accounted for 26% of all cases. Most of the low risk patients (67%) remained free of progression after FCR (Fig. 1B), and their hazard of relapse dropped to zero after 5 years of follow-up. Consistently, the PFS curve of low risk patients plateaued after 5-years from FCR (Fig 1B). The life expectancy of low risk patients (91% at 5 year) was superimposable to that observed in the matched normal general population (Fig. 1D), indicating that neither the disease, nor complications of its treatment affected survival in this favorable group of CLL. Conversely, patients belonging to the intermediate risk (IGHV unmutated and/or 11q deleted) and high risk (17p deleted) categories showed a constant increase of the hazard of progression over time and almost all were projected to relapse after FCR, although at a different rate: 10% per year of follow-up in the intermediate risk group and 17% per year of follow-up in the high risk group (Fig. 1B-C). The 5-year life expectancy of intermediate and high-risk patients was significantly impaired compared to that observed in the matched general population (85% and 60%, respectively) (Fig. 1D), indicating an excess of deaths related to the disease or treatment complications in these unfavorable groups of CLL. Conclusions. The combination of three biomarkers that are routinely tested at treatment allows to segregate a subgroup of CLL (IGHV mutated without 17p or 11q deletion) that may achieve a durable remission after first line FCR treatment and experience an expected survival similar to that of the general population. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3300.3300

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3240-3240

Abstract: Introduction. Elderly patients with chronic lymphocytic leukemia (CLL) and younger patients with comorbidities are often treated with chlorambucil (Chl), despite the relatively low response rates. The addition of anti-CD20 monoclonal antibodies to Chl substantially increases the response rates, without negatively affecting tolerability. Overall response rates (ORR) between 66% to 84% have been reported with these combinations, with complete responses (CR)ranging from 8% to 26%. Methods. We conducted a retrospective analysis on the use of the Chl-rituximab (R) combination as frontline treatment for elderly (≥65 years) and/or unfit (CIRS 〉 6) CLL patients treated at 15 different Italian hematologic centers. The main aim of the study was to further establish the safety and efficacy of the Chl-R protocol and investigate whether certain CLL patients for whom this protocol could be particularly effective could be identified. To this end, we performed a subgroup analysis stratifying patients according to FISH and IGHV results: high risk group (HR) included patients with 17p deletion, intermediate risk group (IR) patients with 11q deletion and/or unmutated IGHV, low risk group (LR) patients without 11q or 17p deletion and/or unmutated IGHV. Results. One hundred and two patients who underwent treatment between 2009 and 2011 were enrolled in the study. Patients' clinical and biologic characteristics are summarized in Table 1. Three patients discontinued treatment earlier than planned: 1 for an episode of autoimmune hemolytic anemia (AIHA) that developed after the 2nd cycle of Chl and before starting R treatment and 2 patients for disease progression after the 3rd and 5th cycle of Chl-R, respectively. The median number of Chl and R cycles administered in the 102 patients was 8 (range 2-12) and 6 (range 1-9), respectively. The planned treatment schedule was different among centers: the two main schedules used were Chl administered at 1 mg/kg for each cycle every 28 days, given at a fixed daily dose of 10 mg starting from day 1 and repeated for 8 cycles, and Chl administered at 8 mg/m2/day for seven days of each of eight 28-day-cycles. R was added to Chl from the 3rd cycle onwards and was administered on day 1 of each cycle at a dose of 375 mg/m2 during the first administration and 500 mg/m2 for the subsequent 5 cycles. On an intention to treat basis, the ORR was 87.1%. Thirty-two patients (31.7%) obtained a CR and 56 patients (55.4%) obtained a partial response (PR). Nostatistically significant differences were noted in terms of ORR for age above or below 70 years, fitness status, ECOG, bulky disease, cytogenetic risk abnormalities, IGHV mutational status, ZAP-70 or CD38 expression.Median progression-free survival (PFS) and time to retreatment (TTR) were reached at 43.7 and 72.3 months, respectively. Median overall survival (OS) was not reached; 86.1% and 81.2% of patients were alive at 48 and 60 months, respectively. The most frequent serious adverse event was grade 3-4 neutropenia, occurring in 13.7% of patients. Grade 3-4 extra-hematologic side effects were uncommon (9.8%). Subgroup analysis of the LR and IR patients (no HR patients were enrolled) showed that LR patients had a significantly better PFS than IR patients (65.8 months vs 35.2 months, p=0.001; Fig. 1),with 54.9% of patients remaining free from progression 60 months after treatment. Conclusions. Treatment of elderly and/or unfit CLL patients with the Chl-R regimen is associated with low toxicity, a high ORR and durable PFS. Particularly good results are achieved in CLL patients with a mutated IGHV profile and not carrying both 17p and 11q deletion, suggesting that in this low-risk subset of unfit patients Chl-R could represent the optimal therapeutic option, in consideration of safety, efficacy and costs. Disclosures D'Arena: Janssen-Cilag: Honoraria. Coscia:Gilead: Honoraria; ROCHE: Honoraria, Other: Advisory board; Janssen: Honoraria; Mundipharma: Honoraria; Karyopharm: Research Funding. Molica:Jansen: Membership on an entity's Board of Directors or advisory committees; Roche Italy: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Speakers Bureau. Efremov:Gilead: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3240.3240

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1782-1782

Abstract: Abstract 1782 The aims of LE.P.RE. study include the identification of clinical and biological factors associated with clinical response and toxicity of lenalidomide monotherapy in relapsed/refractory CLL patients enrolled from 9 Italian centers. Lenalidomide treatment schedule starts with 5 mg daily and increases of 5 mg daily every two weeks, up to 25 mg daily or maximum tolerated dose. Therapy is scheduled to be administered for 12 courses (1 course = 4 weeks) unless disease progression or excessive toxicity are observed. Here we show preliminary results about the first 20 enrolled patients up to the 4th treatment course. Patients received a mean daily lenalidomide dose of 8 mg in the 1st course, 10 mg in the 2nd, 14 mg in the 3rd and 4th. Four patients left the study at the 1st course (1 acute renal failure ARF, 1 infection, 1 second neoplasia likely related to CLL, 1 consent withdrawal) and 3 patients at the 3rd (1 Tumor Flare Reaction TFR, 1 infection, 1 thrombocytopenia). The observed toxicities are listed in Table 1. After the 4th course, 13 patients were evaluable for response: 9 partial response (PR), 3 progressive disease (PD) and 1 stable disease (SD) [ORR 69%]. Table 1 Hematological and extra hematological toxicities (n° tot cases=20) grade n° cases grade n° cases Thrombocytopenia 03/04/11 7 TLS 2 1 Neutropenia 03/04/11 14 TFR 1-2 4 Anemia 03/04/11 2 Second Neoplasia 1 Death 1 ARF 02/03/11 3 Infection 03/04/11 3 We compared the levels of several cytokines measured by ELISA in plasma of the 20 patients at baseline and day+8 of therapy. We observed a significant increase of IL2 Receptor (mean 55,31 vs 112,14 ng/ml; p 〈 0,001), IL2 (14,15 vs 17,27 pg/ml; p=0,019), CCL3 (5,21 vs 21,23 pg/ml; p 〈 0,001), CCL4 (24,76 vs 72,99 pg/ml; p=0,003), IL10 (2,65 vs 6,33 pg/ml; p=0,001), IL1b (0,94 vs 2,77 pg/ml; p=0,048), TNFa (35,00 vs 140,59 pg/ml; p 〈 0,001) and IL8 (0,31 vs 3,50 pg/ml; p=0,037) and a decrease of Thrombospondin 1 (693 vs 488 ng/ml; p=0,037). Interestingly, we found that IL1b level decreased from baseline to day+8 in the 4 non responder (PD+SD) patients while increasing in the 9 responder (PR) patients. Moreover, we found that the 5 patients that experienced TFR or tumor lysis syndrome TLS had significantly higher CCL3 level at baseline than the other 15 patients (p=0,025). We also studied peripheral blood cell subsets (T, B, NK, monocyte, dendritic and endothelial cells) in the 20 patients by flow cytometry. From baseline to day+8 we observed a significant increase of the Thelper1/Thelper2 ratio (p 〈 0,001), T cytotoxic1/Tcytotoxic2 ratio (p=0,001) and memory T cells % (p 〈 0,001) as well as a decrease of naïve T cells % (p 〈 0,001) and mean CD69 expression on T cells (p=0,016). Moreover, the expression of CD40 (p=0,001), CD80 (p=0,018), CD86 (p=0,003) and CD95 (p=0,008) were found to be increased on B-CLL cells. Finally, we observed a decrease of endothelial progenitors cells (EPC) (p=0,032) and live circulating endothelial cells (CEC) (p 〈 0,001) and an increase of dead CEC (p 〈 0,001). Interestingly, there was a significant difference in activated CEC (mean 53,57 vs 81,63 CEC %; p=0,031) and resting CEC (46,54 vs 18,37; p=0,031) at baseline between responders and non responders, respectively. Moreover, the patients exhibiting TFR or TLS showed a higher % of CD4+CD3+ cells (p=0,009) and CD4+CD8+ cells (p=0,036) at day+8 than the others. In conclusion: (i) the increase of inflammatory cytokines IL2R, IL2, CCL3, CCL4, IL10, IL1b and TNFa observed from baseline to day+8 suggests that lenalidomide can induce immune activation; (ii) the augmentation of IL2, IL2R and memory T cells and the decrease of naïve T cells noticed from baseline to day+8 indicate that lenalidomide can promote T cell activation; (iii) the shift toward Thelper1 and Tcytotoxic1 phenotypes and the increased expression of co-stimulatory molecules on B-CLL cells observed from baseline to day+8 suggest that lenalidomide can promote an active T cell response against leukemic cells; (iv) the alterations in EPC and CEC noticed from baseline to day+8 suggest that lenalidomide may also have an anti angiogenic action. Moreover, our preliminary data seem to show interesting biological differences among CLL patients that respond or do not respond to lenalidomide treatment, which if replicated in additional patients and with increasing time on therapy could give important information for predicting which patients may best respond to therapy or may experience TFR or TLS. Disclosures: Maffei: CELGENE CORPORATION: Research Funding. Off Label Use: Lenalidomide, a thalidomide analogue, is an immunomodulatory drug (IMiD) with antitumoural activity reported in various malignant disorders including multiple myeloma and myelodysplastic syndrome. At preclinical level, lenalidomide has shown to decrease the production of several prosurvival cytokines. This drug is also reported to modulate an effector cell immune response through the activation of T and natural killer cells, inducing apoptosis directly on tumour cells. Currently available data indicate that lenalidomide is active also in heavily pre-treated CLL patients. However, in order to reduce toxicity and to optimize the therapeutic index of lenalidomide treatment in CLL patients, it is necessary to identify features of tumour cells that differ between responder and non responder patients. Hence, we propose a multicenter, phase II study designed in order to identify potential predictive factors correlating with response and toxicity to Lenalidomide treatment in relapsed/refractory CLL patients. Martinelli:CELGENE CORPORATION: Research Funding. Debbia:CELGENE CORPORATION: Research Funding. Rigolin:CELGENE CORPORATION: Research Funding. Rizzotto:CELGENE CORPORATION: Research Funding. Castelli:CELGENE CORPORATION: Research Funding. Bonacorsi:CELGENE CORPORATION: Research Funding. Bulgarelli:CELGENE CORPORATION: Research Funding. Fiorcari:CELGENE CORPORATION: Research Funding. Zucchini:CELGENE CORPORATION: Research Funding. Santachiara:CELGENE CORPORATION: Research Funding. Forconi:CELGENE CORPORATION: Research Funding. Rossi:CELGENE CORPORATION: Research Funding. Laurenti:CELGENE CORPORATION: Research Funding. Palumbo:CELGENE CORPORATION: Research Funding. Vallisa:CELGENE CORPORATION: Research Funding. Cuneo:CELGENE CORPORATION: Research Funding. Gaidano:CELGENE CORPORATION: Research Funding. Luppi:CELGENE CORPORATION: Research Funding. Marasca:CELGENE CORPORATION: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.1782.1782

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1260-1260

Abstract: Abstract 1260 Angiopoietin-2 (Ang2) is a 75 kDa secreted glycoprotein able to bind to the receptor tyrosine kinase Tie-2 and detectable especially in vascular remodeling sites. High Ang2 levels are observed in highly vascularized tumors and may play a role in tumor angiogenesis. We have recently demonstrated that Ang2 protein secreted by CLL cells increases in vivo and in vitro angiogenesis and that, in a small CLL cohort, higher Ang2 mRNA expression is associated with advanced stage disease and shorter progression-free survival. In order to further investigate potential prognostic role of Ang2 in CLL, we measured Ang2 plasma levels using an ELISA-based method, in a large multicentric series: 42(13.3%) of 316 analyzed patients had previously received treatment and an additional 53(16.8%) required therapy during the study course, with a median TTFT of 40 months. Ang2 dosage ranged from 972 to 17281 pg/ml (median, 2061 pg/ml). The best cut-off point, generated by ROC analysis and Youden's index (state variable, treating), was 2460 pg/ml and divided our cohort in two subsets (high Ang2 and low Ang2) composed by 100 (31.6%) and 216 (68.4%) patients, respectively. The median TTFT resulted significantly shorter (P 〈 .001) in the high Ang2 subgroup (77.5 months) than in the low one (179.2 months). Cox univariate analysis identified Ang2 ≥ 2460 pg/ml as a predictor of reduced TTFT (HR 2.437; 95%CI 1.621 - 3.664, P 〈 .001) as well as advanced Binet stage, unmutated IGHV status, high CD38, ZAP-70 and CD49d expression, intermediate/high cytogenetic risk and high β2 microglobulin (P 〈 .001 in all instances). Multivariate analysis confirmed that high Ang2 levels were an independent prognosticator for TTFT (HR 1.739; 95%CI 1.059 – 2.857; P=.029) together with inter/high FISH risk (P 〈 .001) and unmutated IGHV status (P= .002). Comparing OS between high Ang2 and low Ang2 subgroup, we found that 26% of high Ang2 patients were dead at 10-years from diagnosis, in contrast with 7% of low Ang2 ones (P=.002). In univariate analysis, Ang2 ≥ 2460 pg/ml resulted to be a predictor of poor OS (HR 3.566; 95%CI 1.496 – 8.499; P=.004) as well as most of the other known unfavorable prognosticators. Significant association was found between high Ang2 plasma level and Binet stages B-C (P 〈 .001), high β2 microglobulin (P 〈 .001), unmutated IGHV status (P 〈 .001), high CD38 and ZAP-70 expression (P 〈 .001 and P=.003, respectively) and inter/high cytogenetic risk (P=.005). However, a relevant percentage of patients showed high Ang2 levels in the presence of favorable markers and vice versa: in this cases, defined as discordant, Ang2 helps to refine prognosis identifying CLL subgroup with precocious need for treatment and reduced survival despite characterized by favorable prognostic factors. In order to evaluate if Ang2 dosage could be modulated by treatment, we compare Ang2 level of plasma samples collected before (n=53) and after (n=42) the first therapy and we did not find any statistical difference (P=.6). Finally, we studied two serial plasma samples collected from 36 patients (median interval, 19 months; range, 3-30 months) and we did not find significant changes in Ang2 level between the two measurements, both for the 7 patients treated inside this interval (P=.612) and for the 29 cases untreated (P=.347). These data first demonstrate the prognostic role of Ang2 plasma level for TTFT and OS in CLL, and shows how Ang2 contributes to refine the prognostic assessment of CLL. The measurement of serial plasma samples demonstrates that Ang2 levels are quite stable during the disease course and are not modulated by current treatments: this suggests that higher Ang2 secretion could be a peculiar biological characteristic of more aggressive CLL, already present in the first disease steps. Our study implies a simple ELISA method, with a high reproducibility and reliability of results, that could be used both for clinical practice and for further studies, in order to better understand CLL pathogenesis and identify new target therapies. Since several molecules targeting microenvironment and angiogenesis are developing in clinical trials for CLL, it could be very interesting to evaluate if they are able to modulate Ang2 secretion and modify the disease clinical aggressiveness. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.1260.1260

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 17, No. 10 ( 2017-10), p. S11-S12

Type of Medium: Online Resource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/j.clml.2017.09.039

Language: English

Publisher: Elsevier BV

Publication Date: 2017

detail.hit.zdb_id: 2540998-0

detail.hit.zdb_id: 2193618-3

In: Leukemia & Lymphoma, Informa UK Limited, Vol. 59, No. 2 ( 2018-02), p. 423-433

Type of Medium: Online Resource

ISSN: 1042-8194 , 1029-2403

URL: Article

DOI: 10.1080/10428194.2017.1339872

Language: English

Publisher: Informa UK Limited

Publication Date: 2018

detail.hit.zdb_id: 2030637-4